PROJECT SUMMARY/ABSTRACT Acne is a disease of the pilosebaceous unit (PSebU) that is ranked third among chronic skin diseases for causing disabilityand is a major cause of psychological impairment and medical expense. The predominant bacterial species in the microbiome of the PSebU is Propionibacterium acnes (aka Cutibacterium acnes), a commensal that can trigger inflammation. This proposal seeks to understand why P. acnespromotes inflammation in only some of the pilosebaceous unit (PSebU) of individuals with acne,yet other individuals do not have disease. To solve this central question of this major human disease and advance fundamental understanding of howP. acnesinteracts with the host immune response, we will study disease-associated phylotypes (PA- acne associated) compared to other strains that do not promote disease (PH- healthy skin associated).The aims of this proposal are based on several important recent discoveries that have shed new light on how P. acnesand the PSebU environment can promote inflammation. PAis shown to preferentially induce pro-inflammatory cytokines IFN-? and IL-17 whereas PHinduces the anti-inflammatory cytokine IL-10in peripheral blood mononuclear cells (PBMC).Complementing this, we have also found that thatwhen P. acnesis placed under anerobic environmental conditions that mimic the plugged PSebU of acne, they then produce short chain fatty acids (SCFAs) that promote cytokine release from keratinocytes (KC). This occurs due to the capacity of some P. acnes strains toinduce epigenetic changes that break immune tolerance of KC to TLR ligands. In this proposal, we will therefore combine our efforts to precisely define mechanisms by which P. acnesinduces inflammation in the PSebU and promotes disease. Our specific aims are: 1) Determine the mechanisms by which the acne microbiome can promote pro- vs. anti-inflammatory responses in lymphoid and myeloid cells, 2) Understand the mechanisms by which metabolites of the acne microbiome induce cytokine responses in KCs and sebocytes; and 3) Determine how strain-specific members of the skin microbiome regulate cutaneous inflammation. The proposed studies will provide new insight into how the skin microbiome shapes cutaneous immune responses leading to inflammation vs. homeostasis, with the potential for intervention in skin disease.